About 1 in every 6 deaths in the United States is due to heart disease resulting in heart attack (myocardial infraction, MI). Patients who survive a heart attack suffer permanent damage to the heart and carry a higher risk of mortality. Stem cell based therapies provide a new tool towards cardiac repair and regeneration that can ultimately enhance health, lengthen life, and reduce the burdens of illness and disability for patients post MI. This proposal is geared towards conducting research at the interface of chemistry and biology with the long term objective to identify drug-like molecules with the ability to induce an endogenous population of stem cells in the adult heart toward cardiac repair post MI. Through extensive research, a lead molecule able to deter the formation of scar tissue (fibrosis) and regenerate heart muscle post MI has been identified. The goal of this proposal is to expand the small molecule library to identify new lead compounds with increased potency and utilize them in synthesizing probes to confirm the biological target as well as seek fundamental knowledge about the nature and behavior of stem cell differentiation. This will in turn set the foundation and basic biological understanding to develop molecules with more drug like characteristics using a more rational approach. To accomplish this goal the following aims are proposed: (1) Design, synthesize, and evaluate analogues of our current lead molecule (2) Evaluate biological data and synthesize photolabeled or radiolabeled probes from lead molecules that can confirm the biological target and assist in the understanding of biological processes and mechanisms involved in stem cell differentiation. Al molecules will be synthesized using cross coupling chemistry reported in the literature and developed in our laboratory. The biological activity will be evaluated through luciferase reporter gene assays. PUBLIC HEALTH RELEVANCE: Cardiovascular disease (CVD) resulting in heart attack (myocardial infarction or MI) is the most common and costly cause of death in the modern world. Patients who survive a heart attack suffer permanent damage to the heart and thus patients are forced to make drastic changes in their lifestyles and carry a higher risk of mortality. Stem cell based therapies provide a new tool towards cardiac repair and regeneration that ultimately enhance health, lengthen life, and reduce the burdens of illness and disability for patients post MI.